Inhibitory Synaptic Plasticity Research Articles

Mimicking Bidirectional Inhibitory Synapse Using a Porous-Confined Ionic Memristor with Electrolyte/Tris(4-aminophenyl)amine Neurotransmitter.

Ionic memristors can emulate brain-like functions of biological synapses for neuromorphic technologies. Apart from the widely studied excitatory-excitatory and excitatory-inhibitory synapses, reports on memristors with the inhibitory-inhibitory synaptic behaviors remain a challenge. Here, the first biaxially inhibited artificial synapse is demonstrated, consisting of a solid electrolyte and conjugated microporous polymers bilayer as neurotransmitter, with the former serving as an ion reservoir and the latter acting as a confined transport. Due to the migration, trapping, and de-trapping of ions within the nanoslits, the device poses inhibitory synaptic plasticity under both positive and negative stimuli. Remarkably, the artificial synapse is able to maintain a low level of stable nonvolatile memory over a long period of time (≈60min) after multiple stimuli, with feature-inferencing/-training capabilities of neural node in neuromorphic computing. This work paves a reliable strategy for constructing nanochannel ionic memristive materials toward fully inhibitory synaptic devices.

Dynamic and selective engrams emerge with memory consolidation

Episodic memories are encoded by experience-activated neuronal ensembles that remain necessary and sufficient for recall. However, the temporal evolution of memory engrams after initial encoding is unclear. In this study, we employed computational and experimental approaches to examine how the neural composition and selectivity of engrams change with memory consolidation. Our spiking neural network model yielded testable predictions: memories transition from unselective to selective as neurons drop out of and drop into engrams; inhibitory activity during recall is essential for memory selectivity; and inhibitory synaptic plasticity during memory consolidation is critical for engrams to become selective. Using activity-dependent labeling, longitudinal calcium imaging and a combination of optogenetic and chemogenetic manipulations in mouse dentate gyrus, we conducted contextual fear conditioning experiments that supported our model’s predictions. Our results reveal that memory engrams are dynamic and that changes in engram composition mediated by inhibitory plasticity are crucial for the emergence of memory selectivity.

GluD1 binds GABA and controls inhibitory plasticity.

Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation, and type A γ-aminobutyric acid receptors (GABAARs), which are responsible for neuronal inhibition. However, the GluD1 receptor, an iGluR family member, is present at both excitatory and inhibitory synapses. Whether and how GluD1 activation may affect inhibitory neurotransmission is unknown. In this work, by using a combination of biochemical, structural, and functional analyses, we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs. GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring. The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticity challenges the classical dichotomy between glutamatergic and GABAergic receptors.

Amyloid Pathology Impairs Experience-Dependent Inhibitory Synaptic Plasticity.

Alzheimer's disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experience in vivo in the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by subtle broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.

Tailoring Neuroplasticity in a Ferroelectric‐Gated Multi‐Terminal Synaptic Transistor by Bi‐Directional Modulation for Improved Pattern Edge Recognition

AbstractThe dynamic modulation of the plasticity of artificial neuromorphic devices facilitates a wide range of neuromorphic functions. However, integrating diverse plasticity modulation techniques into a single device presents a challenge due to limitations in the device structure design. Here, a multiterminal artificial synaptic device capable of bi‐directional modulation on its plasticity is proposed. Significantly, the conversion of inhibitory and excitatory synaptic plasticity can be achieved not only by modifying the polarity of the presynaptic voltage spike but also by exchanging its input terminal between top and bottom gate while maintaining the same presynaptic stimuli. This unique bi‐directional modulation of synaptic plasticity has been attributed to two distinct physical mechanisms: nonvolatile ferroelectric polarization and interface charge trap‐induced memory characteristics. Additionally, the effective dynamic modulation of the synaptic behaviors is quantified under different back‐gate bias and verified in the constructed neural network perceptron. Further, a visual simulation demonstrates the enhanced clarity and precision of edge recognition through the back‐gate modulation in the artificial synapses. This study provides a strategy to fulfill diversified modulation on synaptic plasticity in ferroelectric‐gated transistors, thereby prompting efficient and controllable neuromorphic visual systems.

Emulating Synaptic and Nociceptive Behavior via Negative Photoconductivity of a Memristor

In comparison to electrical memristive synapses, photoelectric synapses have the capability for ultrafast computing with less power consumption. In this work, a photoelectric synaptic memristor (PSM) based on Zn <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$_{{\text{2}}}$</tex-math> </inline-formula> SnO <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$_{{\text{4}}}$</tex-math> </inline-formula> (ZSO)/cuprous oxide (Cu <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$_{{\text{2}}}$</tex-math> </inline-formula> O) heterostructure is fabricated. This two-terminal PSM device with a simple structure exhibits primary synaptic functions such as long-term potentiation (LTP)/long-term depression (LTD), and spike-timing-dependent plasticity (STDP) by electrical stimulation. Under the exposure of violet light, the observed negative persistent photoconductivity (NPPC) of our PSM is associated with inhibitory synaptic plasticity, which leads to synaptic performances such as short to long-term memory (STM-LTM) transition, learning experience behavior, and a transition from post-tetanic potentiation (PTP) to post-tetanic depression (PTD). Furthermore, this PSM mimics the five essential features of a nociceptive receptor (nociceptor) like threshold, relaxation, no-adaptation, hyperalgesia, and allodynia in response to violet light pulse-induced NPPC phenomenon. These results provide a new path to propel the development of neuro-inspired perceptual systems.

Reconfigurable Artificial Synapse Based on Ambipolar Floating Gate Memory.

Artificial synapse networks capable of massively parallel computing and mimicking biological neural networks can potentially improve the processing efficiency of existing information technologies. Semiconductor devices functioning as excitatory and inhibitory synapses are crucial for developing intelligence systems, such as traffic control systems. However, achieving reconfigurability between two working modes (inhibitory and excitatory) and bilingual synaptic behavior in a single transistor remains challenging. This study successfully mimics a bilingual synaptic response using an artificial synapse based on an ambipolar floating gate memory comprising tungsten selenide (WSe2)/hexagonal boron nitride (h-BN)/ molybdenum telluride (MoTe2). In this WSe2/h-BN/MoTe2 structure, ambipolar semiconductors WSe2 and MoTe2 are inserted as channel and floating gates, respectively, and h-BN serves as the tunneling barrier layer. Using either positive or negative pulse amplitude modulations at the control gate, this device with bipolar channel conduction produced eight distinct resistance states. Based on this, we experimentally projected that we could achieve 490 memory states (210 hole-resistance states + 280 electron-resistance states). Using the bipolar charge transport and multistorage states of WSe2/h-BN/MoTe2 floating gate memory, we mimicked reconfigurable excitatory and inhibitory synaptic plasticity in a single device. Furthermore, the convolution neural network formed by these synaptic devices can recognize handwritten digits with an accuracy of >92%. This study identifies the unique properties of heterostructure devices based on two-dimensional materials as well as predicts their applicability in advanced recognition of neuromorphic computing.

UNC-43/CaMKII-triggered anterograde signals recruit GABAARs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs

Disturbed inhibitory synaptic transmission has functional impacts on neurodevelopmental and psychiatric disorders. An essential mechanism for modulating inhibitory synaptic transmission is alteration of the postsynaptic abundance of GABAARs, which are stabilized by postsynaptic scaffold proteins and recruited by presynaptic signals. However, how GABAergic neurons trigger signals to transsynaptically recruit GABAARs remains elusive. Here, we show that UNC-43/CaMKII functions at GABAergic neurons to recruit GABAARs and modulate inhibitory synaptic transmission at C. elegans neuromuscular junctions. We demonstrate that UNC-43 promotes presynaptic MADD-4B/Punctin secretion and NRX-1α/Neurexin surface delivery. Together, MADD-4B and NRX-1α recruit postsynaptic NLG-1/Neuroligin and stabilize GABAARs. Further, the excitation of GABAergic neurons potentiates the recruitment of NLG-1-stabilized-GABAARs, which depends on UNC-43, MADD-4B, and NRX-1. These data all support that UNC-43 triggers MADD-4B and NRX-1α, which act as anterograde signals to recruit postsynaptic GABAARs. Thus, our findings elucidate a mechanism for pre- and postsynaptic communication and inhibitory synaptic transmission and plasticity.

Increasing Selectivity to a Feature Combination Using Inhibitory Synaptic Plasticity in a Spiking Neural Network.

Increasing Selectivity to a Feature Combination Using Inhibitory Synaptic Plasticity in a Spiking Neural Network.

SCN1A gain of function causes interneuron hyperexcitability and network instability through inhibitory synaptic plasticity in early infantile encephalopathy.

SCN1A gain-of-function variants are associated with early infantile and neonatal-onset developmental and epileptic encephalopathies (DEE). It is unclear how SCN1A gain-of-function may predispose to cortical hyper-excitability and seizures. We studied the biophysical properties of four pathogenic Nav1.1 variants associated with neonatal-onset (T162I, I236V) or early infantile (P1345S, R1636Q) DEE. In voltage clamp experiments, the activation curves of the variants were either unchanged (T236V), or exhibited hyperpolarized shifts (T162I, P1345S, R1636Q), corresponding to gain-of-function through enhanced window currents. Inactivation curves were unchanged (I236V, P1345S), depolarized, suggesting gain-of-function (R1636Q), or hyperpolarized, suggesting loss-of-function (T162I). Dynamic action potential clamp experiments supported a gain of function mechanism for all variants. Model neurons incorporating Nav1.1. channels with properties of I236V, P1345S, or R1636Q variants exhibited higher and sustained firing relative to wild type, whereas T162I exhibited enhanced early action potential firing and depolarization block. T162I and R1636Q produced a hyperpolarized threshold and reduced neuronal rheobase. To explore the impact of SCN1A variants upon cortical excitability, we used a cortical network model containing excitatory pyramidal cells, PV interneurons and realistic synaptic connectivity. SCN1A gain-of-function was modelled by enhancing PV excitability and incorporating a simple form of homeostatic adaptation: inhibitory synaptic plasticity. Although both wild-type and gain-of-function networks possessed similar basal pyramidal cell firing rates, the gain-of-function network was more sensitive to external perturbation and exhibited synchronous epileptiform-like activity. Further analysis revealed that reduced synaptic strength results in a deficit of feedback inhibition and an increased excitatory-inhibitory ratio in the gain-of-function network. Overall, our findings support the role of SCN1A gain-of-function in early onset DEE. We propose a mechanism through which homeostatic adaptations in neuronal networks can predispose to enhanced excitatory activity and seizures.

Experience-dependent plasticity of gustatory insular cortex circuits and taste preferences.

Early experience with food influences taste preference in adulthood. How gustatory experience influences development of taste preferences and refinement of cortical circuits has not been investigated. Here, we exposed weanling mice to an array of taste solutions and determined the effects on the preference for sweet in adulthood. We demonstrate an experience-dependent shift in sucrose preference persisting several weeks following the termination of exposure. A shift in sucrose palatability, altered neural responsiveness to sucrose, and inhibitory synaptic plasticity in the gustatory portion of the insular cortex (GC) were also induced. The modulation of sweet preference occurred within a restricted developmental window, but restoration of the capacity for inhibitory plasticity in adult GC reactivated the sensitivity of sucrose preference to taste experience. Our results establish a fundamental link between gustatory experience, sweet preference, inhibitory plasticity, and cortical circuit function and highlight the importance of early life nutrition in setting taste preferences.

Optogenetics-inspired manipulation of synaptic memory using all-optically controlled memristors.

Memristive synapses compatible with optogenetic techniques allow for the fast and low-power manipulation of memory activities using light in artificial neural systems. However, most of the optoelectronic memristors operate in the hybrid optic-electric mode; the reversible regulation of memristive states solely using light for optogenetic emulation is difficult. In this work, an all-optical controlled optoelectronic memristor (Au/Cs2AgBiBr6/Au) is developed for mimicking optogenetics-tuned memory formation and erasing behaviors in biological synapses. We show that the memristor exhibits positive and negative persistent photoconductivity effects under different light wavelengths, attributed to light-regulated carrier de-trapping/trapping at the Au/Cs2AgBiBr6 interface. This device can emulate both excitatory and inhibitory synaptic plasticity and associated learning and memory effects under light illumination. We constructed a prototype optoelectronic synaptic array and implemented the all-optically controlled memory implantation, erasing, and modification, demonstrating the light-reconfigured cognition capabilities. Our findings will inspire the development of all-optically controlled artificial neural systems with good reconfigurability for efficient neuromorphic computing and machine vision.

Scandium Nitride as a Gateway III‐Nitride Semiconductor for both Excitatory and Inhibitory Optoelectronic Artificial Synaptic Devices

AbstractTraditional computation based on von Neumann architecture is limited by time and energy consumption due to data transfer between the storage and the processing units. The von Neumann architecture is also inefficient in solving unstructured, probabilistic, and real‐time problems. To address these challenges, a new brain‐inspired neuromorphic computational architecture is required. Due to the absence of resistance–capacitance delay, high bandwidth, and low power consumption, optoelectronic artificial synaptic devices are highly attractive. Yet, stable, scalable, and complementary metal–oxide–semiconductor (CMOS)‐compatible materials exhibiting both inhibitory and excitatory optoelectronic synaptic functionalities have not been demonstrated. Here, epitaxial CMOS‐compatible scandium nitride (ScN) optoelectronic artificial synaptic devices that emulate both inhibitory and excitatory biological synaptic activities are presented. The negative and positive persistent photoconductivity of undoped and magnesium‐doped ScN is equated to the inhibitory and excitatory synaptic plasticity, respectively, which leads to functionalities like learning–forgetting, frequency‐selective optical filtering, frequency‐dependent potentiation and depression, Hebbian learning, and logic‐gate operations. Temperature‐dependent photoresponse and photo‐Hall measurements reveal that scattering of photogenerated carriers from charged defect centers results in negative photoconductivity in undoped degenerate ScN. This work opens up the possibility of utilizing a group‐III epitaxial semiconducting nitride material with inhibitory and excitatory optoelectronic synaptic functionalities for practical neuromorphic applications.

The biological alterations of synapse/synapse formation in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a common complication caused by sepsis, and is responsible for increased mortality and poor outcomes in septic patients. Neurological dysfunction is one of the main manifestations of SAE patients. Patients may still have long-term cognitive impairment after hospital discharge, and the underlying mechanism is still unclear. Here, we first outline the pathophysiological changes of SAE, including neuroinflammation, glial activation, and blood-brain barrier (BBB) breakdown. Synapse dysfunction is one of the main contributors leading to neurological impairment. Therefore, we summarized SAE-induced synaptic dysfunction, such as synaptic plasticity inhibition, neurotransmitter imbalance, and synapses loss. Finally, we discuss the alterations in the synapse, synapse formation, and mediators associated with synapse formation during SAE. In this review, we focus on the changes in synapse/synapse formation caused by SAE, which can further understand the synaptic dysfunction associated with neurological impairment in SAE and provide important insights for exploring appropriate therapeutic targets of SAE.

Altered Expression and In Vivo Activity of mGlu5 Variant a Receptors in the Striatum of BTBR Mice: Novel Insights Into the Pathophysiology of Adult Idiopathic Forms of Autism Spectrum Disorders.

mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of "monogenic" forms of autism spectrum disorders (ASD), such as Fragile- X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects. Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD, and behavioral phenotype. Behavioral tests were associated with biochemistry analysis including qPCR and western blot for mRNA and protein expression. In vivo analysis of polyphosphoinositides hydrolysis was performed to study the mGlu5-mediated intracellular signaling in the striatum of adult BTBR mice under basal conditions and after MTEP exposure. Expression of mGlu5 receptors and mGlu5 receptor-mediated polyphosphoinositides hydrolysis were considerably high in the striatum of BTBR mice, sensitive to MTEP treatment. Changes in the expression of genes encoding for proteins involved in excitatory and inhibitory neurotransmission and synaptic plasticity, including Fmr1, Dlg4, Shank3, Brd4, bdnf-exon IX, Mef2c, and Arc, GriA2, Glun1, Nr2A, and Grm1, Grm2, GriA1, and Gad1 were also found. Behaviorally, BTBR mice showed high repetitive stereotypical behaviors, including self-grooming and deficits in social interactions. Acute or repeated injections with MTEP reversed the stereotyped behavior and the social interaction deficit. Similar effects were observed with the NMDA receptor blockers MK-801 or ketamine. These findings support a pivotal role of mGlu5 receptor abnormal expression and function in idiopathic ASD adult forms and unveil novel potential targets for therapy.

Sleep and wake cycles dynamically modulate hippocampal inhibitory synaptic plasticity.

Sleep is an essential process that consolidates memories by modulating synapses through poorly understood mechanisms. Here, we report that GABAergic synapses in hippocampal CA1 pyramidal neurons undergo daily rhythmic alterations. Specifically, wake inhibits phasic inhibition, whereas it promotes tonic inhibition compared to sleep. We further utilize a model of chemically induced inhibitory long-term potentiation (iLTP) to examine inhibitory plasticity. Intriguingly, while CA1 pyramidal neurons in both wake and sleep mice undergo iLTP, wake mice have a much higher magnitude. We also employ optogenetics and observe that inhibitory inputs from parvalbumin-, but not somatostatin-, expressing interneurons contribute to dynamic iLTP during sleep and wake. Finally, we demonstrate that synaptic insertion of α5-GABAA receptors underlies the wake-specific enhancement of iLTP at parvalbumin-synapses, which is independent of time of the day. These data reveal a previously unappreciated daily oscillation of inhibitory LTP in hippocampal neurons and uncover a dynamic contribution of inhibitory synapses in memory mechanisms across sleep and wake.

Chloride transporters controlling neuronal excitability.

Synaptic inhibition plays a crucial role in regulating neuronal excitability, which is the foundation of nervous system function. This inhibition is largely mediated by the neurotransmitters GABA and glycine that activate Cl--permeable ion channels, which means that the strength of inhibition depends on the Cl- gradient across the membrane. In neurons, the Cl- gradient is primarily mediated by two secondarily active cation-chloride cotransporters (CCCs), NKCC1 and KCC2. CCC-mediated regulation of the neuronal Cl- gradient is critical for healthy brain function, as dysregulation of CCCs has emerged as a key mechanism underlying neurological disorders including epilepsy, neuropathic pain, and autism spectrum disorder. This review begins with an overview of neuronal chloride transporters before explaining the dependent relationship between these CCCs, Cl- regulation, and inhibitory synaptic transmission. We then discuss the evidence for how CCCs can be regulated, including by activity and their protein interactions, which underlie inhibitory synaptic plasticity. For readers who may be interested in conducting experiments on CCCs and neuronal excitability, we have included a section on techniques for estimating and recording intracellular Cl-, including their advantages and limitations. Although the focus of this review is on neurons, we also examine how Cl- is regulated in glial cells, which in turn regulate neuronal excitability through the tight relationship between this nonneuronal cell type and synapses. Finally, we discuss the relatively extensive and growing literature on how CCC-mediated neuronal excitability contributes to neurological disorders.

Co-exposure of melamine and cyanuric acid as a risk factor for oxidative stress and energy metabolism: Adverse effects on hippocampal neuronal and synaptic function induced by excessive ROS production

Melamine (MEL) and cyanuric acid (CA) alone have relatively low toxicity, but together they may cause serious damage to multiple organs, including the central nervous system, however, the underlying mechanism is unknown. This study aimed to determine and compare the neurotoxic effects of MEL (20 μg/mL), CA (20 μg/mL) and their combination (10 μg/mL MEL and 10 μg/mL CA) on cultured hippocampal neurons. The cell viability, apoptosis, anti-oxidative and energy metabolic indices were detected following 24 h of incubations. The miniature excitatory postsynaptic currents (mEPSCs), miniature inhibitory postsynaptic currents (mIPSCs) and synaptic plasticity in the hippocampal CA1 neurons were recorded. Moreover, ROS scavenger NAC was co-infused to investigate the potential mechanism. We found the complex of MEL and CA but not their alone caused severe cell death and disturbed energy production through activation caspase-3-mediated apoptosis. Meanwhile, the combination significantly reduced the amplitude, decay time and frequency of mEPSCs but not mIPSCs, indicating the pre- and post-synaptic inhibitory actions on neuronal activity. Paired-pulsed ratio (PPR) and long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses were critically depressed. However, the co-application of NAC could effectively mitigate the cellular apoptosis, energy metabolism dysfunction and the impairments in neuronal and synaptic function. Our findings provide the first evidence that the combination of MEL and CA can exert more prominently neurotoxic effects than their alone and certify that one of the potential mechanisms for neuronal and synaptic dysfunction is the ROS-mediated signaling pathway.

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins.

Neuronal activity initiates signaling cascades that culminate in diverse outcomes including structural and functional neuronal plasticity, and metabolic changes. While studies have revealed activity-dependent neuronal cell type-specific transcriptional changes, unbiased quantitative analysis of cell-specific activity-induced dynamics in newly synthesized proteins (NSPs) synthesis in vivo has been complicated by cellular heterogeneity and a relatively low abundance of NSPs within the proteome in the brain. Here we combined targeted expression of mutant MetRS (methionine tRNA synthetase) in genetically defined cortical glutamatergic neurons with tight temporal control of treatment with the noncanonical amino acid, azidonorleucine, to biotinylate NSPs within a short period after pharmacologically induced seizure in male and female mice. By purifying peptides tagged with heavy or light biotin-alkynes and using direct tandem mass spectrometry detection of biotinylated peptides, we quantified activity-induced changes in cortical glutamatergic neuron NSPs. Seizure triggered significant changes in ∼300 NSPs, 33% of which were decreased by seizure. Proteins mediating excitatory and inhibitory synaptic plasticity, including SynGAP1, Pak3, GEPH1, Copine-6, and collybistin, and DNA and chromatin remodeling proteins, including Rad21, Smarca2, and Ddb1, are differentially synthesized in response to activity. Proteins likely to play homeostatic roles in response to activity, such as regulators of proteastasis, intracellular ion control, and cytoskeleton remodeling proteins, are activity induced. Conversely, seizure decreased newly synthetized NCAM, among others, suggesting that seizure induced degradation. Overall, we identified quantitative changes in the activity-induced nascent proteome from genetically defined cortical glutamatergic neurons as a strategy to discover downstream mediators of neuronal plasticity and generate hypotheses regarding their function.SIGNIFICANCE STATEMENT Activity-induced neuronal and synaptic plasticity are mediated by changes in the protein landscape, including changes in the activity-induced newly synthesized proteins; however, identifying neuronal cell type-specific nascent proteome dynamics in the intact brain has been technically challenging. We conducted an unbiased proteomic screen from which we identified significant activity-induced changes in ∼300 newly synthesized proteins in genetically defined cortical glutamatergic neurons within 20 h after pharmacologically induced seizure. Bioinformatic analysis of the dynamic nascent proteome indicates that the newly synthesized proteins play diverse roles in excitatory and inhibitory synaptic plasticity, chromatin remodeling, homeostatic mechanisms, and proteasomal and metabolic functions, extending our understanding of the diversity of plasticity mechanisms.

Developmental depression-to-facilitation shift controls excitation-inhibition balance

Changes in the short-term dynamics of excitatory synapses over development have been observed throughout cortex, but their purpose and consequences remain unclear. Here, we propose that developmental changes in synaptic dynamics buffer the effect of slow inhibitory long-term plasticity, allowing for continuously stable neural activity. Using computational modeling we demonstrate that early in development excitatory short-term depression quickly stabilises neural activity, even in the face of strong, unbalanced excitation. We introduce a model of the commonly observed developmental shift from depression to facilitation and show that neural activity remains stable throughout development, while inhibitory synaptic plasticity slowly balances excitation, consistent with experimental observations. Our model predicts changes in the input responses from phasic to phasic-and-tonic and more precise spike timings. We also observe a gradual emergence of short-lasting memory traces governed by short-term plasticity development. We conclude that the developmental depression-to-facilitation shift may control excitation-inhibition balance throughout development with important functional consequences.